Comparison of ESTs from juvenile and adult phases of the giant unicellular green alga Acetabularia acetabulum

BACKGROUND: Acetabularia acetabulum is a giant unicellular green alga whose size and complex life cycle make it an attractive model for understanding morphogenesis and subcellular compartmentalization. The life cycle of this marine unicell is composed of several developmental phases. Juvenile and adult phases are temporally sequential but physiologically and morphologically distinct. To identify genes specific to juvenile and adult phases, we created two subtracted cDNA libraries, one adult-specific and one juvenile-specific, and analyzed 941 randomly chosen ESTs from them. RESULTS: Clustering analysis suggests virtually no overlap between the two libraries. Preliminary expression data also suggests that we were successful at isolating transcripts differentially expressed between the two developmental phases and that many transcripts are specific to one phase or the other. Comparison of our EST sequences against publicly available sequence databases indicates that ESTs from the adult and the juvenile libraries partition into different functional classes. Three conserved sequence elements were common to several of the ESTs and were also found within the genomic sequence of the carbonic anhydrase1 gene from A. acetabulum. To date, these conserved elements are specific to A. acetabulum. CONCLUSIONS: Our data provide strong evidence that adult and juvenile phases in A. acetabulum vary significantly in gene expression. We discuss their possible roles in cell growth and morphogenesis as well as in phase change. We also discuss the potential role of the conserved elements found within the EST sequences in post-transcriptional regulation, particularly mRNA localization and/or stability

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control

An Interactive Perceptual Rendering Pipeline using Contrast and Spatial Masking

International audienceWe present a new perceptual rendering pipeline which takes into account visual masking due to contrast and spatial frequency. Our framework predicts inter-object, scene-level masking caused by partial occlusion and shadows. It is designed for interactive applications and runs efficiently on the GPU. This is achieved using a layer-based approach together with an efficient GPU-based computation of threshold maps. We build upon this prediction framework to introduce a perceptually-based level of detail control algorithm. We conducted a perceptual user study which indicates that our perceptual pipeline generates results which are consistent with what the user perceives. Our results demonstrate significant quality improvement for scenes with masking due to frequencies and contrast, such as masking due to trees or foliage, or due to high-frequency shadows

Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman’s rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients. Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes

Metastable Se6 as a ligand for Ag+: from isolated molecular to polymeric 1D and 2D structures

Attempts to prepare the hitherto unknown Se6 2+ cation by the reaction of elemental selenium and Ag[A] ([A]- = [Sb(OTeF5)6]-, [Al(OC(CF3)3)4]-) in SO2 led to the formation of [(OSO)Ag(Se6)Ag(OSO)][Sb(OTeF5)6]2 1 and [(OSO)2Ag(Se6)Ag(OSO)2][Al(OC(CF3)3)4]2 2a. 1 could only be prepared by using bromine as co-oxidant, however, bulk 2b (2a with loss of SO2) was accessible from Ag[Al(OC(CF3)3)4] and grey Se in SO2 (chem. analysis). The reactions of Ag[MF6] (M= As, Sb) and elemental selenium led to crystals of 1/∞{[Ag(Se6)]∞[Ag2(SbF6)3]∞} 3 and {1/∞[Ag(Se6)Ag]∞}[AsF6]2 4. Pure bulk 4 was best prepared by the reaction of Se4[AsF6]2, silver metal and elemental selenium. Attempts to prepare bulk 1 and 3 were unsuccessful. 1–4 were characterized by single-crystal X-ray structure determinations, 2b and 4 additionally by chemical analysis and 4 also by X-ray powder diffraction, FT-Raman and FT-IR pectroscopy. Application of the PRESTO III sequence allowed for the first time 109Ag MAS NMR investigations of 4 as well as AgF, AgF2, AgMF6 and {1/∞[Ag(I2)]∞}[MF6] (M= As, Sb). Compounds 1 and 2a/b, with the very large counter ions, contain isolated [Ag(Se6)Ag]2+ heterocubane units consisting of a Se6 molecule bicapped by two silver cations (local D3d sym). 3 and 4, with the smaller anions, contain close packed stacked arrays of Se6 rings with Ag+ residing in octahedral holes. Each Ag+ ion coordinates to three selenium atoms of each adjacent Se6 ring. 4 contains [Ag(Se6)+]∞ stacks additionally linked by Ag(2)+ into a two dimensional network. 3 features a remarkable 3-dimensional [Ag2(SbF6)3]- anion held together by strong Sb–F … Ag contacts between the component Ag+ and [SbF6]- ions. The hexagonal channels formed by the [Ag2(SbF6)3]- anions are filled by stacks of [Ag(Se6)+]∞ cations. Overall 1–4 are new members of the rare class of metal complexes of neutral main group elemental clusters, in which the main group element is positively polarized due to coordination to a metal ion. Notably, 1 to 4 include the commonly metastable Se6 molecule as a ligand. The structure, bonding and thermodynamics of 1 to 4 were investigated with the help of quantum chemical calculations (PBE0/TZVPP and (RI-)MP2/TZVPP, in part including COSMO solvation) and Born–Fajans–Haber-cycle calculations. From an analysis of all the available data it appears that the formation of the usually metastable Se6 molecule from grey selenium is thermodynamically driven by the coordination to the Ag+ ions

The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry

Objectives: Chronic non-bacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder characterized by sterile bone osteolytic lesions. The aim of this study was to evaluate the demographic data and clinical, instrumental and therapeutic features at baseline in a large series of CNO/CRMO patients enrolled in the Eurofever registry. Methods: A web-based registry collected retrospective data on patients affected by CRMO/CNO. Both paediatric and adult centres were involved. Results: Complete baseline information on 486 patients was available (176 male, 310 female). The mean age of onset was 9.9 years. Adult onset (>18 years of age) was observed in 31 (6.3%) patients. The mean time from disease onset to final diagnosis was 1 year (range 0-15). MRI was performed at baseline in 426 patients (88%), revealing a mean number of 4.1 lesions. More frequent manifestations not directly related to bone involvement were myalgia (12%), mucocutaneous manifestations (5% acne, 5% palmoplantar pustulosis, 4% psoriasis, 3% papulopustular lesions, 2% urticarial rash) and gastrointestinal symptoms (8%). A total of 361 patients have been treated with NSAIDs, 112 with glucocorticoids, 61 with bisphosphonates, 58 with MTX, 47 with SSZ, 26 with anti-TNF and 4 with anakinra, with a variable response. Conclusion: This is the largest reported case series of CNO patients, showing that the range of associated clinical manifestations is rather heterogeneous. The study confirms that the disease usually presents with an early teenage onset, but it may also occur in adults, even in the absence of mucocutaneous manifestations

Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Babesia divergens glycosylphosphatidylinositols modulate blood coagulation and induce Th2-biased cytokine profiles in antigen presenting cells

This work was supported by the the University of Tours (to IDP and FDG), the University of Montpellier (to SD and EC), the Deutsche Forschungsgemeinschaft (to RTS), the Wellcome Trust project grant 093228 (to TKS) and the Campus France/DAAD PHC PROCOPE 24931RE (to RTS and EC). The funding source has no involvement in the conduct of the research and preparation of the article.Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs.Publisher PDFPeer reviewe

Deglacial diatom productivity and surface ocean properties over the Bermuda Rise, northeast Sargasso Sea

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 24 (2009): PA4101, doi:10.1029/2008PA001729.Diatom assemblages document surface hydrographic changes over the Bermuda Rise. Between 19.2 and 14.5 ka, subtropical diatom species and Chaetoceros resting spores dominate the flora, as in North Atlantic productive regions today. From 16.9 to 14.6 ka, brackish and fresh water diatoms are common and their contribution is generally coupled with total diatom abundance. This same interval also contains rare grains of ice-rafted debris. Coupling between those proxies suggests that successive discharge of icebergs might have stimulated productivity during Heinrich event 1 (H1). Iceberg migration to the subtropics likely created an isolated environment involving turbulent mixing, upwelled water, and nutrient-rich meltwater, supporting diatom productivity in an otherwise oligotrophic setting. In addition, the occurrence of mode water eddies likely brought silica-rich waters of Southern Ocean origin to the euphotic zone. The persistence of lower-salinity surface water beyond the last ice rafting suggests continued injection of fresh water by cold-core rings and advection around the subtropical gyre. These results indicate that opal productivity may have biased estimates of meridional overturning based on 231Pa/230Th ratios in Bermuda Rise sediments during H1.Support for this research was provided by the Fundação para a Ciência e Tecnologia through the grant BPD/27214/2006 to I. M. Gil